Non-alcoholic steatohepatitis (NASH) is an important cause of liver related morbidity. Given that obese and type 2 diabetic patients are at risk and these processes are common in the U.S., the impact of research aimed at finding a therapy is far reaching. By virtue of its antioxidant properties, Silymarin may have a plausible role as an effective therapy for NASH, a process in which oxidant injury has been implicated. Therefore, the broad aims of this research are to establish the safety, tolerability, and efficacy of Silymarin in NASH patients with two of the most commonly associated disorders, obesity and type 2 diabetes. The first part of the Phase I study is a dose-finding study using a sequence of escalating doses with alternating groups of obese patients with NASH. This study design aims to assess the safety, tolerability, and pharmacokinetic profile of silibinin at steady state conditions at a maximally tolerated dose of Silymarin. The primary endpoints of this study will be the incidence of adverse events and the pharmacokinetic parameter of AUC(0-12hr). The second part of phase I will assess the safety and tolerability of Silymarin in type 2 diabetics with NASH, studied separately from the obese patients due to the potential interacting effect of oral hypoglycemics. Specifically, we will compare the pharmacokinetic parameter of AUC(0-12hr) and the incidence of adverse events in obese patients with NASH to type 2 diabetics with NASH who are treated with oral secretagogues (sulfonylureas, repaglinide, nateglinide, glimepiride) with or without insulin. The phase II study will comprise a 48 week placebo controlled double blind randomized trial of Silymarin in patients with NASH and obesity or type 2 diabetes. The primary endpoint will be the improvement in hepatic histology, compared to baseline, in Silymarin versus placebo treated patients. [unreadable] Relevance to Public Health: This research addresses an increasingly common problem in a large segment of the U.S. population; that is, liver injury caused by fat in obese and diabetic patients. Silymarin has been used for many centuries for the treatment of liver diseases and has been shown to be safe. This research will prove the safety and effectiveness of Silymarin for liver injury caused by fat in obese and diabetic patients, in carefully designed scientific trials. These results will allow practitioners and patients to decide whether to use Silymarin in this specific disease process. [unreadable] [unreadable] [unreadable]